Sjogren's syndrome (SS) is a common, complex autoimmune disorder characterized by lymphocytic infiltration into exocrine glands causing dry mouth and eyes, fatigue, malaise, and polyarthritis. Diagnosis of SS remains challenging and limited therapeutic options often culminate in irreversible destruction of the exocrine glands. SS shares many clinical and immunological similarities with other autoimmune diseases including systemic lupus erythematosus and rheumatoid arthritis, Though large-scale genetic and genomic studies performed in these other diseases have proven enormously successful in identifying novel target pathways and loci associated with disease, the genetics of SS are woefully unexplored, giving us an opportunity to make an important contribution toward conquering this enigmatic disease. With the guidance, assistance and resources provided by the Oklahoma Sjogren's Syndrome Centers for Research Translation (OSSCORT), we will use state-of-the-art genetic and analytical tools to integrate extensive laboratory, clinical and genetic data to identify and characterize the molecular basis of etiology and pathogenesis of human SS. Specifically, we propose to 1) test for association of SS with genetic variants previously shown to be association with SLE and other autoimmune diseases using the ImmunoChip; 2) perform genome-wide association studies to identify novel candidate loci associated with SS susceptibility and disease subphenotypes through integrative analyses of genetic, genomic, laboratory and clinical data, and 3) establish novel robust genetic associations with SS through replication in independent cohorts. We will exploit our substantial infrastructure and network of multidisciplinary experts to achieve these goals. No other group in the world has the sample sizes, volume of clinical data, or concentration of expertise to conduct these studies. At the completion of Project 1, we will provide new genes with fundamental insights into the mechanisms regarding etiology of SS. At the same time, the infrastructure developed through this OSSCORT will provide the basis for and have profound effects on future investigations in SS and potentially related autoimmune disease.